N.Morisot, K.Rouibi et A. Contarino dans Neuropsychopharmaco

Le 1 avril 2015

CRF2 Receptor-Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal. Morisot N, Rouibi K, Contarino A. Neuropsychopharmacology. 2015 Feb 12. doi: 10.1038/npp.2015.49.

Angelo Contarino: Drug addiction is a chronic relapsing disorder associated with deregulated up-shifted motivational states and high risk of relapse even after prolonged drug-free periods. Stressful life events may trigger the reappearance of up-shifted motivational states, contributing to drug seeking, craving and relapse to drug intake. A better understanding of the neural mechanisms underlying the persistent vulnerability to stress during long-term drug abstinence may help the development of effective therapy for drug addiction. In mammalians, stress responses are orchestrated by the corticotrophin-releasing factor (CRF) system, through two distinct receptors, CRF1 and CRF2.

The CRF receptors also differentially contribute to opiate addiction-like behaviors in mouse models (Contarino and Papaleo, 2005; Papaleo et al, 2007; Ingallinesi et al, 2012). We recently found that opiate-withdrawn mice show an up-shifted motivation to obtain a natural food reward during the early phase of opiate withdrawal (Rouibi and Contarino 2012, which is attenuated by the genetic deletion of the CRF2 receptor (Rouibi and Contarino 2013). In the present study, we examined the role for the CRF2 receptor in the long-lasting vulnerability to stress that may precipitate up-shifted motivational states, even following long-term opiate withdrawal. We found that two different ethological environmental stressors (i.e. withdrawing food reward from an operant chamber test or exposure to an elevated platform stress) dramatically trigger the reemergence of increased non-rewarded nose-pokes, reflecting up-shifted motivational states, long after cessation of morphine administration in mice.

We also found that the stress-induced reemergence of up-shifted motivational states is associated with an increase in the biosynthesis of brain markers relevant to motivational states, such as ventral tegmental area (VTA)-dopamine (DA) and amygdala-γ-aminobutyric acid (GABA) systems. However, genetic inactivation of the CRF2 receptor abolishes both the behavioral expression and the neural substrates of the stress-induced reemergence of motivational states following long-term opiate withdrawal.

Our work reveals thus a major role for the CRF/CRF2 receptor pathway in the long-lasting vulnerability to stress induced by drug withdrawal and suggests totally new strategies to effectively treat drug addiction. Indeed, blocking the CRF2 receptor may prevent the reemergence of up-shifted motivational states triggered by stressful life events during prolonged drug-free periods, thus helping former drug users to remain drug-abstinent

Angelo Contarino